First-line Non-nucleoside Reverse Transcriptase Inhibitor Research Articles

Dolutegravir plus boosted darunavir versus recommended standard-of-care antiretroviral regimens in people with HIV-1 for whom recommended first-line non-nucleoside reverse transcriptase inhibitor therapy has failed (D2EFT): an open-label, randomised, phase 3b/4 trial

Randomised comparative data on efficacy and safety of second-line antiretroviral therapy (ART) after failure of non-nucleoside reverse transcriptase inhibitors (NNRTIs) across diverse geographical settings are scarce. The aim of this study was to evaluate optimal second-line ART for people with HIV. D2EFT is a completed international, randomised, open-label, phase 3b/4 trial evaluating three second-line ART strategies in adults (aged ≥18 years) with HIV-1 for whom first-line NNRTI therapy has failed. The study was done at 28 sites across 14 countries in Asia, Africa, and Latin America. It was originally designed to compare recommended standard of care (ritonavir-boosted darunavir [800 mg darunavir plus 100 mg ritonavir once daily] plus two nucleoside reverse transcriptase inhibitors [NRTIs; dosed once or twice daily]) with a novel nucleoside sparing regimen of dolutegravir (50 mg once daily) with ritonavir-boosted darunavir. The study was adapted during the first year to add a third arm of dolutegravir (50 mg once daily) with fixed tenofovir disoproxil fumarate (300 mg once daily) plus either lamivudine (300 mg once daily) or emtricitabine (200 mg once daily). Participants were randomly assigned with a computer-generated, blocked randomisation scheme (block size of two) stratified by site, previous tenofovir disoproxil fumarate use, and HIV viral load. The trial was designed to evaluate non-inferiority of either interventional arm against standard of care for the primary outcome of virological suppression, as determined by HIV RNA load of less than 50 copies per mL at 48 weeks. The prespecified non-inferiority margin was 12%. Comparisons were made with a modified intention-to-treat population, including all participants randomly assigned but excluding administrative withdrawals. This study is registered with ClinicalTrials.gov, NCT03017872. 1190 individuals were screened; 828 participants were enrolled between Nov 1, 2017, and Dec 31, 2021. Two participants were unable to receive their assigned regimen for administrative reasons; and 826 participants were included in analyses. Median age was 39 years (IQR 33-46), and 450 (54%) participants were female. Baseline median CD4 count was 206 cells per μL (23-354) and median HIV RNA was 15 400 copies per mL (3600-65 986). The proportion of participants with HIV RNA of less than 50 copies per mL at 48 weeks was 194 (75%) of 257 in the ritonavir-boosted darunavir plus two NRTIs group, 222 (84%) of 264 in the ritonavir-boosted darunavir plus dolutegravir group, and 227 (78%) of 291 in the dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine group. Compared with ritonavir-boosted darunavir plus two NRTIs, the difference in virological suppression was 8·6% (95% CI 1·7 to 15·5; p=0·016) for dolutegravir plus ritonavir-boosted darunavir and 6·7% (-1·2 to 14·4; p=0·093) for dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine. Six deaths occurred, none of which were related to treatment. 19 pregnancies (11 livebirths) occurred with no congenital defects. In individuals experiencing failure of an NNRTI-based first-line ART, a switch to either dolutegravir plus ritonavir-boosted darunavir or dolutegravir with tenofovir disoproxil fumarate plus either lamivudine or emtricitabine, without universal access to genotyping, was non-inferior in achieving viral suppression compared with ritonavir-boosted darunavir plus two NRTIs. These global data support the most recent WHO treatment guidelines. UNITAID; National Institute of Allergy and Infectious Diseases, USA; National Health and Medical Research Council, Australia; ViiV Healthcare; and Janssen.

Clinical outcomes with second-line dolutegravir in people with virological failure on first-line non-nucleoside reverse transcriptase inhibitor-based regimens in South Africa: a retrospective cohort study

Dolutegravir (DTG) is recommended for second-line antiretroviral therapy (ART) after virological failure on first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens in people living with HIV in low-income and middle-income countries. We compared the effectiveness of DTG versus the previously recommended ritonavir-boosted lopinavir (LPV/r) regimen for second-line treatment in South Africa. In this retrospective observational cohort study, we used routinely collected, de-identified data from 59 primary health-care facilities in eThekwini Municipality, KwaZulu-Natal, South Africa. We included people living with HIV aged 15 years or older with virological failure (defined as two consecutive viral loads of ≥1000 copies per mL at least 56 days apart) on first-line NNRTI-based ART containing tenofovir disoproxil fumarate (TDF) and who switched to second-line ART. Our primary outcomes were retention in care and viral suppression (<50 copies per mL) at 12 months after starting second-line treatment. We used modified Poisson regression models to compare these outcomes between second-line regimens (zidovudine [AZT]/emtricitabine or lamivudine [XTC]/DTG; TDF/XTC/DTG; and AZT/XTC/LPV/r). We included 1214 participants in our study, of whom 729 (60%) were female and 485 (40%) were male, and whose median age was 36 years (IQR 30-42). 689 (57%) were switched to AZT/XTC/LPV/r, 217 (18%) to AZT/XTC/DTG, and 308 (25%) to TDF/XTC/DTG. Compared with AZT/XTC/LPV/r (75%), retention in care was higher with AZT/XTC/DTG (86%, adjusted risk ratio [aRR]=1·14, 95% CI 1·03-1·27; adjusted risk difference [aRD]=10·89%, 95% CI 2·01 to 19·78) but similar with TDF/XTC/DTG (77%, aRR=1·01, 0·94-1·10; aRD=1·04%, -5·03 to 7·12). Observed retention in care was lower with TDF/XTC/DTG than with AZT/XTC/DTG, although in multivariable analysis evidence for a difference was weak (aRR=0·89, 0·78-1·01, p=0·060; aRD=-9·85%, -20·33 to 0·63, p=0·066). Of 799 participants who were retained in care with a 12-month viral load test done, viral suppression was higher with AZT/XTC/DTG (59%; aRR=1·25, 1·06-1·47; aRD=11·57%, 2·37 to 20·76) and higher with TDF/XTC/DTG (61%; aRR=1·30, 1·14-1·48; aRD=14·16%, 7·14 to 21·18) than with AZT/XTC/LPV/r (47%). These findings from routine care support further implementation of WHO's recommendation to use DTG instead of LPV/r in people living with HIV who experience virological failure while receiving first-line NNRTI-based ART. Bill & Melinda Gates Foundation. For the isiZulu translation of the abstract see Supplementary Materials section.

Adaption of an ongoing clinical trial to quickly respond to gaps in changing international recommendations: the experience of D2EFT

A rapidly changing landscape of antiretrovirals and their procurement at scale has permitted the evaluation of new optimised second-line antiretroviral therapy (ART) in low- and middle-income countries. D2EFT is an open-label randomised controlled non-inferiority phase IIIB/IV trial in people living with HIV-1 (PWH) whose first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART is failing. At inception, it compared a standard of care of boosted darunavir with two nucleos(t)ide reverse transcriptase inhibitors (NRTIs) to the novel NRTI-sparing regimen of boosted darunavir with dolutegravir. Implemented in 2017, participating sites were across Africa, Asia and Latin America. Around the time of implementation, the World Health Organization updated its treatment guidelines and recommended scaling up tenofovir disoproxil fumarate-lamivudine-dolutegravir (TLD). This situation pushed D2EFT investigators to consider the impact of the roll-out of TLD on the D2EFT research question. The protocol team agreed it was important to study TLD in second-line when an NNRTI regimen was failing, and focused on options to expedite the work by studying the question within the existing trial and network. All key issues (statistical, programmatic and financial) were reviewed to assess the benefits and risks of adding a third arm to the ongoing study, as opposed to developing a new randomised clinical trial with the same control arm and within the same network. The development of a new trial was deemed to be longer than adding a third arm, and to create a challenging situation with two competing clinical trials at the same sites which would slow down recruitment and impair both trials. On the other hand, adding a third arm would be demanding in terms of operationalisation, increased sample size and statistical biases to control. The optimal strategy was deemed to be the addition of a third arm, arriving retrospectively at a simplified multi-arm multi-stage clinical trial design to achieve statistical validity. The D2EFT study maintains additional value in a quickly evolving second-line ART strategy allowed by the progress in global access to ART.

High Level of Pretreatment and Acquired Human Immunodeficiency Virus Drug Resistance in El Salvador: A Nationally Representative Survey, 2018-2019.

Human immunodeficiency virus drug resistance (HIVDR) can negatively impact the effectiveness of antiretroviral therapy (ART). We aimed to estimate the prevalence of pretreatment HIVDR (PDR) among ART initiators and the prevalence of viral load (VL) suppression and acquired HIVDR among individuals receiving ART for 12 ± 3 months (ADR12) and ≥48 months (ADR48) in El Salvador. Nationally representative cross-sectional PDR, ADR12 and ADR48 surveys were conducted among adults with HIV from October 2018 to August 2019, following World Health Organization-recommended methods. Demographic and clinic data and blood specimens were collected. Two hundred sixty participants were enrolled in the PDR survey, 230 in ADR12 and 425 in ADR48. Twenty-seven percent (95% confidence interval [CI], 17.1%-39.9%) of ART initiators had PDR to efavirenz or nevirapine. The prevalence of VL suppression was 88.8% (95% CI, 83.1%-92.8%) in ADR12 and 80.5% (95% CI, 76.6%-84.0%) in ADR48 surveys. Among people with HIV receiving a first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based ART regimens and with unsuppressed VL, the prevalence of ADR to efavirenz or nevirapine was 72.0% (95% CI, 32.3%-93.3%) and 95.0% (68.5%-99.4%) in the ADR12 and ADR28 surveys, respectively. ADR12 to boosted protease inhibitors (PI/r) or integrase strand transfer inhibitors (INSTIs) was not observed. ADR48 was 1.3% (95% CI, 0.2%-9.6%) and 2.1% (0.3%-13.7%), respectively. Programmatic improvements in ART delivery are urgently needed in El Salvador to address the high levels of resistance to efavirenz or nevirapine among ART initiators and the low VL suppression prevalence among individuals on treatment.

Near-point-of-care assay with a visual readout for detection of HIV-1 drug resistance mutations: A proof-of-concept study

Human immunodeficiency virus (HIV) infection is a chronic disease that can be treated with antiretroviral (ARV) therapy. However, the success of this treatment has been jeopardized by the emergence of HIV infections resistant to ARV drugs. In low-to middle-income countries (LMICs), where transmission of resistant viruses has increased over the past decade, there is an urgent need to improve access to HIV drug resistance testing. Here, we present a proof-of-concept study of a rapid and simple molecular method to detect two major mutations (K103 N, Y181C) conferring resistance to first-line nonnucleoside reverse transcriptase inhibitor regimens. Our near-point-of-care (near-POC) diagnostic test, combining a sequence-specific primer extension and a lateral flow DNA microarray strip, allows visual detection of HIV drug resistance mutations (DRM) in a short turnaround time (4 h 30). The assay has a limit of detection of 100 copies of plasmid DNA and has a higher sensitivity than standard Sanger sequencing. The analytical performance was assessed by use of 16 plasma samples from individuals living with HIV-1 and results demonstrated the specificity and the sensitivity of this approach for multiplex detection of the two DRMs in a single test. Furthermore, this near-POC assay could be easily taylored to detect either new DRMs or DRM of from various HIV clades and might be useful for pre-therapy screening in LMICs with high levels of transmitted drug resistance.

Healthcare resource utilization and costs in patients with HIV-1 who switched first-line antiretroviral therapy

Objectives: This study compared healthcare utilization and costs associated with switching the first-line protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) based antiretroviral (ARV) regimen due to reasons other than virologic failure among patients with HIV-1.Methods: This was a retrospective analysis of commercial and Medicare Advantage with Part D enrollees in two US administrative claims databases. The study population comprised adults with HIV-1 infection initiating antiretroviral therapy (ART) on PI- or NNRTI-containing regimens from 1 January 2006 to 31 December 2015. Patients with a subsequent change in anchor agent were assigned to the switch cohort; the non-switch cohort was constructed using propensity score matching of three non-switching patients for each patient in the switch cohort. Patient characteristics and per patient per month healthcare resource utilization and costs were compared between the cohorts during the pre-switch, switch (15 days before and after switching) and post-switch periods. Costs during the switch period were also estimated with a multivariable-adjusted model.Results: The matched study population consisted of 1204 patients who switched their first-line PI- or NNRTI-based regimen and 3612 patients who did not. Compared with the non-switch cohort, patients who switched had higher healthcare resource utilization during the pre-switch, switch and post-switch periods. Mean unadjusted non-ART costs in the switch cohort were nearly double ($2944 versus $1530, p < .001), more than double ($2562 versus $1215, p < .001) and 1.5 times higher ($1473 versus $968, p < .001) than costs in the non-switch cohort in the pre-switch, switch and post-switch periods, respectively.Conclusions: Patients with HIV-1 who initiated PI- or NNRTI-based regimens and switched ARTs for reasons other than virologic failure used more healthcare resources and incurred greater costs relative to patients in the non-switch cohort. This study highlights the importance of initiating patients on appropriate first-line ART to avoid the need to switch due to reasons other than virologic failure.

Factors associated with mortality in HIV patients failing antiretroviral therapy, in Salvador, Brazil

Highly active antiretroviral therapy (HAART) has significantly improved survival of people living with HIV/Aids (PLWHA). However, poor treatment adherence to HAART and other problems, still cause therapy failure and contribute to increased morbidity and mortality of PLWHA. In this retrospective cohort study (2013–2015), we sought to evaluate the factors associated with mortality of PLWHA failing HAART in 2013, who were receiving care at a reference center for sexually transmitted diseases (STD) and HIV/AIDS. A total of 165 individuals over 18 years of age who were failing antiretroviral therapy were evaluated. In two-year follow-up, 19 (11.5%) deaths were documented. There were a significant association between mortality and report of illicit drug use (53%, p < 0.01), being attended by a larger number of medical professionals (6.3 ± 3.2, p = 0.02), use of firstline non-nucleoside reverse transcriptase inhibitor (74%, p = 0.01), and history of interrupting HAART ≥3 months (90%), p = 0.02). Patients who died had a significantly higher viral load (mean 49,192.4 ± 35,783.6 copies/mL) than survivors (26,389.2 ± 27,416 copies/mm3, p < 0.01), lower mean CD4 cell counts (127.8 ± 145.6 cells/mm3 vs. 303.3 ± 202.4 cells/mm3, p < 0.01), and higher frequency of previous virologic failure (89% vs. 74.7%, p < 0.01). Our results reinforce the importance of early detection and prevention of virologic failure, to reduce the mortality associated with this event.

Maternal side effects of efavirenz-containing highly active antiretroviral therapy (HAART): A comparative study of HIV-positive pregnant and nonpregnant women in a tertiary hospital

Background: Efavirenz is now a first-line non-nucleoside reverse transcriptase inhibitor used as highly active antiretroviral therapy (HAART) though its use is fraught with maternal side effects, usually of the central nervous system (CNS) and fetal complications.Objective: The study aims to comparatively document the maternal side-effect profile of an efavirenz-containing fixed-dosage HAART and compliance with its use in HIV-positive pregnant and nonpregnant women at the Lagos University Teaching Hospital (LUTH), Idi-Araba.Methodology: A prospective study among HIV-positive pregnant (40) and nonpregnant women (40) on efavirenz-containing fixed-dose HAART (Atripla®) who were recruited purposively at the antenatal clinic and AIDS Prevention Initiative Nigeria (APIN) clinics of LUTH. Data analysis was done with EPI Info 2014, and the results are presented in frequencies.Results: The mean age of respondents was 31 ± 5.7 years. Atripla® was the only fixed-dose combination used. Fifty-three percent and 62.5% of pregnant and nonpregnant HIV-positive women, respectively, reported CNS side effects of Atripla® [odds ratio: 0.66, 95% confidence interval 0.27–1.62]. Adherence to the use of Atripla® was 100% among HIV-positive pregnant women. Women with baseline viral load values greater than 400 copies/mL reported more side effects to Atripla®.Conclusion: There are similar side-effect profiles of Atripla® in HIV-positive women irrespective of pregnancy. Education and counselling can help foster adherence, resulting in improved immunological and virological outcome.

Drug Resistance-Associated Mutations in Antiretroviral Treatment-Experienced Patients in Kuwait

Objectives: To investigate the prevalence of nonpolymorphic resistance-associated mutations (RAM) in HIV-1 patients on first-line antiretroviral therapy in Kuwait. Subjects and Methods: Total RNA was isolated from plasma samples of 42 patients who received a first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen. HIV-1 protease and reverse transcriptase genetic regions were then amplified by nested reverse transcription-polymerase chain reaction and directly sequenced. The HIV-1 subtype was identified using the Bayesian phylogenetic method, and RAM were identified using the Stanford University genotypic resistance interpretation algorithm. Results: The HIV-1 viral load at sampling ranged from < 20 to 8.25 × 10⁴ copies/ml. CRF01_AE, C, and B were the most predominant HIV-1 subtypes. Nonpolymorphic mutations associated with resistance to antiretroviral drugs were detected in 11 (26.2%) of the 42 patients; 5 (11.9%) patients had mutations associated with a high-level resistance to nucleoside reverse transcriptase inhibitors (NRTI), 4 (9.5%) patients had mutations associated with resistance to NNRTI, 1 (2.4%) patient had mutations associated with resistance to both NRTI and NNRTI, and 1 (2.4%) patient had mutations potentially associated with low-level resistance to both protease inhibitors and NNRTI. All patients with RAM had a detectable plasma HIV-1 RNA level. Conclusion: Our results indicate the development of RAM during an NNRTI-based regimen and highlight the importance of considering other regimens to avoid treatment failure.

Comparative efficacy and safety of second-line antiretroviral therapy for treatment of HIV/AIDS: a systematic review and network meta-analysis

Selection of optimal second-line antiretroviral therapy (ART) has important clinical and programmatic implications. To inform the 2016 revision of the WHO ART guidelines, we assessed the comparative effectiveness and safety of available second-line ART regimens for adults and adolescents in whom first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens have failed. In this systematic review and network meta-analysis, we searched for randomised controlled trials and prospective and retrospective cohort studies that evaluated outcomes in treatment-experienced adults living with HIV who switched ART regimen after failure of a WHO-recommended first-line NNRTI-based regimen. We searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Trials for reports published from Jan 1, 1996, to Aug 8, 2016, and searched conference abstracts published from Jan 1, 2014, to Aug 8, 2016. Outcomes of interest were viral suppression, mortality, AIDS-defining illnesses or WHO stage 3-4 disease, discontinuations, discontinuations due to adverse events, and serious adverse events. We assessed comparative efficacy and safety in a network meta-analysis, using Bayesian hierarchical models. We identified 12 papers pertaining to eight studies, including 4778 participants. The network was centred on ritonavir-boosted lopinavir plus two nucleoside or nucleotide reverse transcriptase inhibitors. Ritonavir-boosted lopinavir monotherapy was the only regimen inferior to others. With the lower estimate of the 95% credible interval (CrI) not exceeding the predefined threshold of 15%, evidence at 48 weeks supported the non-inferiority of ritonavir-boosted lopinavir plus raltegravir to regimens including ritonavir-boosted protease inhibitor plus two NRTIs with respect to viral suppression (odds ratio 1·09, 95% CrI 0·88-1·35). Estimated efficacy of ritonavir-boosted darunavir (800 mg once daily) was too imprecise to determine non-inferiority. Overall, regimens did not differ significantly with respect to continuations, AIDS-defining illnesses or WHO stage 3-4 disease, or mortality. With the exception of ritonavir-boosted lopinavir plus raltegravir, the evidence base is unable to provide strong support to alternative second-line options to ritonavir-boosted protease inhibitor plus two NRTIs, and thus more trials are warranted. WHO.

Contribution of APOBEC3G/F activity to the development of low-abundance drug-resistant human immunodeficiency virus type 1 variants

Plasma drug-resistant minority human immunodeficiency virus type 1 variants (DRMVs) increase the risk of virological failure to first-line non-nucleoside reverse transcriptase inhibitor antiretroviral therapy (ART). The origin of DRMVs in ART-naive patients, however, remains unclear. In a large pan-European case–control study investigating the clinical relevance of pre-existing DRMVs using 454 pyrosequencing, the six most prevalent plasma DRMVs detected corresponded to G-to-A nucleotide mutations (V90I, V106I, V108I, E138K, M184I and M230I). Here, we evaluated if such DRMVs could have emerged from apolipoprotein B mRNA editing enzyme, catalytic polypeptide 3G/F (APOBEC3G/F) activity. Out of 236 ART-naive subjects evaluated, APOBEC3G/F hypermutation signatures were detected in plasma viruses of 14 (5.9%) individuals. Samples with minority E138K, M184I, and M230I mutations, but not those with V90I, V106I or V108I, were significantly associated with APOBEC3G/F activity (Fisher's P < 0.005), defined as the presence of > 0.5% of sample sequences with an APOBEC3G/F signature. Mutations E138K, M184I and M230I co-occurred in the same sequence as APOBEC3G/F signatures in 3/9 (33%), 5/11 (45%) and 4/8 (50%) of samples, respectively; such linkage was not found for V90I, V106I or V108I. In-frame STOP codons were observed in 1.5% of all clonal sequences; 14.8% of them co-occurred with APOBEC3G/F signatures. APOBEC3G/F-associated E138K, M184I and M230I appeared within clonal sequences containing in-frame STOP codons in 2/3 (66%), 5/5 (100%) and 4/4 (100%) of the samples. In a re-analysis of the parent case control study, the presence of APOBEC3G/F signatures was not associated with virological failure. In conclusion, the contribution of APOBEC3G/F editing to the development of DRMVs is very limited and does not affect the efficacy of non-nucleoside reverse transcriptase inhibitor ART.

Oligonucleotide ligation assay detects HIV drug resistance associated with virologic failure among antiretroviral-naive adults in Kenya.

Transmitted drug resistance (TDR) is increasing in some areas of Africa. Detection of TDR may predict virologic failure of first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy (ART). We evaluated the utility of a relatively inexpensive oligonucleotide ligation assay (OLA) to detect clinically relevant TDR at the time of ART initiation. Pre-ART plasmas from ART-naive Kenyans initiating an NNRTI-based fixed-dose combination ART in a randomized adherence trial conducted in 2006 were retrospectively analyzed by OLA for mutations conferring resistance to NNRTI (K103N, Y181C, and G190A) and lamivudine (M184V). Post-ART plasmas were analyzed for virologic failure (≥1000 copies/mL) at 6-month intervals over 18-month follow-up. Pre-ART plasmas of those with virologic failure were evaluated for drug resistance by consensus and 454-pyrosequencing. Among 386 participants, TDR was detected by OLA in 3.89% (95% confidence interval: 2.19 to 6.33) and was associated with a 10-fold higher rate of virologic failure (hazard ratio: 10.39; 95% confidence interval: 3.23 to 32.41; P < 0.001) compared with those without TDR. OLA detected 24 TDR mutations (K103N: n = 13; Y181C: n = 5; G190A: n = 3; M184V: n = 3) in 15 subjects (NNRTI: n = 15; 3TC: n = 3). Among 51 participants who developed virologic failure, consensus sequencing did not detect additional TDR mutations conferring high-level resistance, and pyrosequencing only detected additional mutations at frequencies <2%. Mutant frequencies <2% at ART initiation were significantly less likely to be found at the time of virologic failure compared with frequencies ≥2% (22% vs. 63%; P < 0.001). Detection of TDR by a point mutation assay may prevent the use of suboptimal ART.

Delayed switch of antiretroviral therapy after virologic failure associated with elevated mortality among HIV-infected adults in Africa.

Routine monitoring of plasma HIV RNA among HIV-infected patients on antiretroviral therapy (ART) is unavailable in many resource-limited settings. Alternative monitoring approaches correlate poorly with virologic failure and can substantially delay switch to second-line therapy. We evaluated the impact of delayed switch on mortality among patients with virologic failure in Africa. A cohort. We examined patients with confirmed virologic failure on first-line nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimens from four cohorts with serial HIV RNA monitoring in Uganda and South Africa. Marginal structural models aimed to estimate the effect of delayed switch on mortality in a hypothetical trial in which switch time was randomly assigned. Inverse probability weights adjusted for measured confounders including time-updated CD4+ T-cell count and HIV RNA. Results: Among 823 patients with confirmed virologic failure, the cumulative incidence of switch 180 days after failure was 30% [95% confidence interval (CI) 27-33]. The majority of patients (74%) had not failed immunologically as defined by WHO criteria by the time of virologic failure. Adjusted mortality was higher for individuals who remained on first-line therapy than for those who had switched [odds ratio (OR) 2.1, 95% CI 1.1-4.2]. Among those without immunologic failure, the relative harm of failure to switch was similar (OR 2.4; 95% CI 0.99-5.8) to that of the entire cohort, although of borderline statistical significance. Among HIV-infected patients with confirmed virologic failure on first-line ART, remaining on first-line therapy led to an increase in mortality relative to switching. Our results suggest that detection and response to confirmed virologic failure could decrease mortality.

P33: Rilpivirine resistance mutations in patients failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) treatments in Argentina

P33: Rilpivirine resistance mutations in patients failing first-line non-nucleoside reverse transcriptase inhibitor (NNRTI) treatments in Argentina

Incidence and determinants of nevirapine and efavirenz-related skin rashes in West Africans: nevirapine's epitaph?

Non-nucleoside reverse transcriptase inhibitor (NNRTI) associated rash is common and frequently leads to discontinuation of NNRTIs. This study assessed the risk of developing rashes and discontinuing NNRTIs and associated factors in a large clinic in central Ghana. In this retrospective cohort study, clinical data were obtained in patients starting efavirenz or nevirapine between 2004–2010. Factors associated with rashes were explored using a multivariate Cox proportional hazards regression model. Of 3,999 patients who started NNRTI-based ART, 281 (7.0%) experienced at least one episode of NNRTI-related rash with an incidence of 2.63 events/100 person-years, occurring in 10.2% and 5.6% of patients taking nevirapine and efavirenz respectively. Most rashes (94%) were grade 1 or 2 and were reported a median of 2 months following initiation of ART. In multivariate analysis developing a rash was associated with nevirapine use (aHR 1.67, 95% CI 1.28–2.10), female gender (aHR of 1.39, 95% CI 1.01–1.92) and lower baseline CD4 counts (aHR 0.88, 95% CI 0.82–0.95 per 50 cells/mm3 increment). Patients with nevirapine-associated rash were 11 times more likely to discontinue treatment as patients with efavirenz-associated rash. In contrast to findings in other studies, NNRTI-associated rashes in Ghanaians appear more common in patients with lower baseline CD4 counts. Given the increased frequency of rashes with nevirapine and subsequent discontinuations in many patients, along with other treatment-limiting toxicities, this provides further impetus for the replacement of nevirapine by efavirenz as the first-line NNRTI treatment of choice in Africa.

Ritonavir-Boosted Lopinavir as Maintenance Monotherapy in HIV-Infected Patients Who Achieved Viral Suppression during a Second-Line Protease Inhibitor–Based Regimen

Eligibility criteria were (1) having previously failed first-line nonnucleoside reverse transcriptase inhibitor–based regimens and (2) having achieved virologic suppression &gt;6 months while receiving a protease inhibitor (PI)-based regimen as second-line treatment. Eligible participants were randomized to receive either (1) ritonavir-boosted lopinavir (LPV/r) monotherapy (n = 29) or (2) LPV/r with optimized background regimens (OBRs; n = 31). Median duration of viral suppression before randomization was 45 months. At week 48, viral suppression during LPV/r monotherapy was 86.2% and did not differ from the suppression achieved with LPV/r with OBRs (87.1%, P = 1.000). However, persistent viremia during LPV/r monotherapy tended to be higher than during LPV/r with OBRs (10.3% versus 3.2%, P = .346). History of viral blip during virologic suppression with second-line PI-based regimen is a predictor of achieving viral suppression at all visits (adjusted relative risk 0.255 [95% confidence interval 0.080-0.821], P = .022). Use of LPV/r monotherapy as maintenance regimen in this study produced persistent viremia that tended to be higher than LPV/r monotherapy with OBRs.

Long-term effectiveness of first-line non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral therapy in Ghana

Information on the long-term effectiveness and tolerability of efavirenz- or nevirapine-based antiretroviral therapy (ART) in Africa is lacking. The primary objective of this retrospective observational study was to compare the long-term clinical and immunological outcomes of efavirenz- versus nevirapine-based first-line ART in a large government clinic in Ghana. The main outcomes were AIDS, death, ART-related toxicity, discontinuation of ART and a composite endpoint of death, AIDS or ART discontinuation. These time-to-event outcomes were compared using a Cox proportional hazards regression model. CD4 counts on ART were compared using a mixed-effects model. A total of 3990 patients started non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART between 2004 and 2010, of which 2369 (59%) were on efavirenz. No significant differences were apparent between each NNRTI for subsequent risk of AIDS, death or the composite of treatment failure; however, stavudine use was independently associated with an increased risk of death [adjusted hazard ratio (HR) 1.60 (95% CI: 1.21-2.11)]. There was an increased risk of early toxicity with nevirapine leading to discontinuation [adjusted HR 1.53 (95% CI: 1.23-1.97)], mostly due to excess skin rashes in the first 2 months of treatment; however, overall discontinuation rates were low. There was no difference in the long-term effectiveness of efavirenz- and nevirapine-based ART in this population; however, patients initiating nevirapine were more likely to develop early toxicity and discontinue this drug. The excess mortality observed in patients taking stavudine is of concern and should prompt increased efforts to replace it with alternative antiretroviral drugs in developing countries.

Predictors of Response to Second-Line Therapy — Do the NRTIs Matter?

The optimal management of patients who experience virologic failure on first-line nonnucleoside reverse-transcriptase inhibitor (NNRTI)-containing

Rilpivirine Resistance-Associated Mutations Among Antiretroviral-Naive Patients Infected With HIV-1 in Asia

Rilpivirine Resistance-Associated Mutations Among Antiretroviral-Naive Patients Infected With HIV-1 in Asia

Second-Line Protease Inhibitor-Based Antiretroviral Therapy after Non-Nucleoside Reverse Transcriptase Inhibitor Failure: The Effect of a Nucleoside Backbone

Virological failures on combined antiretroviral therapy still occur. Boosted protease inhibitor ( Pl/r)- based therapy is a commonly used option after non-nucleoside reverse transcriptase inhibitor ( NNRTI) failure, but whether two fully active nucleoside reverse transciptase inhibitors (NRTIs) are required is unknown. We investigated the effect of an NRTI backbone in individuals receiving Pl/r after failing NNRTI-based combined antiretroviral therapy. A longitudinal analysis of the UK Collaborative HIV Cohort (CHIC) and the UK HIV Drug Resistance Database to identify individuals who failed first-line NNRTI and two NRTIs, and switched to Pl/r-based therapy between January 1999 and December 2008 was conducted. We investigated the effect of NRTI on suppression. In total, 470 individuals met study criteria: 19.6%, 34.5% and 46.0% started 0, 1 or ≥ 2 NRTIs, respectively. Median CD4+ T-cell count was 223 cells/mm3 and HIV-RNA was 4.3 log10 copies/ml; 246 (52.3%) underwent genotyping before switch. virological failure occurred in 10.9% and 13% after 48 and 96 weeks, respectively. In multivariable analysis, heterosexual risk group and HIV RNA were independently associated with virological failure; higher CD4+ T-cell count was protective (HR= 0.92). Number of new NRTIs or genotypic sensitivity score of backbone had no effect on treatment success rates when modelled as categorical or continuous variables. Successful treatment with a second-line Pl/r may not require two active NRTIs. If replicated in clinincal trials, these findings could guide future recommendations.